Synthetic protocols and circular dichroism (CD) spectra are reported for a series of oligomers of
(R,R)-trans-2-aminocyclopentanecarboxylic acid (trans-ACPC). The two longest oligomers, a hexamer and
an octamer, have also been examined crystallographically. Both crystal structures show that the β-peptide
backbone adopts a regular helix that is defined by a series of interwoven 12-membered ring hydrogen bonds
(“12-helix”). Each hydrogen bond links a carbonyl oxygen to an amide proton three residues toward the
C-terminus. CD data suggest that the conformational preference of trans-ACPC oligomers in methanol is
strongly length-dependent, which implies that 12-helix formation is a cooperative process, as seen for the
α-helix formed by conventional peptides. Previous work has established that oligomers and polymers of β-amino
acids can adopt helical conformations, but the 12-helix is an unprecedented β-peptide secondary structure.
The preparation, crystal structures, and circular dichroism (CD) spectra of two oligomers of optically
active trans-2-aminocyclohexanecarboxylic acid are reported. In the solid state, both the tetramer and the
hexamer of this β-amino acid display a helical conformation that involves 14-membered-ring hydrogen bonds
between a carbonyl oxygen and the amide proton of the second residue toward the N-terminus. (For comparison,
the familiar α-helix observed in conventional peptides is associated with a 13-membered-ring hydrogen bond
between a carbonyl oxygen and the amide proton of the fourth residue toward the C-terminus.) These
crystallographic data, along with CD data obtained in methanol, suggest that the 14-helix constitutes a stable
secondary structure for β-amino acid oligomers (“β-peptides”). In addition, the crystal packing pattern observed
for the hexamer offers a blueprint for the design of β-peptides that might adopt a helical bundle tertiary structure.
We examine the relationship between covalent structure and conformational propensity among a series of β-amino acid tetramers. These experiments focus on the hairpin folding motif. Among conventional peptides, the minimum increment of β-sheet secondary structure is a "β-hairpin," in which two strands are connected via a short loop. The present studies are aimed at optimizing hairpin stability among β-peptides. Previous work from our laboratory has identified optimal substitution patterns for residues that form strands in an antiparallel β-peptide sheet (Krautha ¨user et al. J. Am. Chem. Soc. 1997, 119, 11719), and we have shown that a dinipecotic acid segment can promote sheet-type interactions between attached strand residues (Chung et al.
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